WHO guideline

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guideline WHO

on the dairy protein content in ready-to-use therapeutic foods

for treatment of uncomplicated

severe acute malnutrition

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guideline WHO

on the dairy protein content in ready-to-use therapeutic foods

for treatment of uncomplicated

severe acute malnutrition

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WHO guideline on the dairy protein content in ready-to-use therapeutic foods for treatment of uncomplicated severe acute malnutrition

ISBN 978-92-4-002227-0 (electronic version) ISBN 978-92-4-002228-7 (print version)

© World Health Organization 2021

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Cover photo by Jean-Philippe Delberghe on Unsplash Design by minimum graphics

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List of tables

Table 1. GRADE evidence profile 19

Table 2. Standard RUTF formulation cost estimates (2013) 23 Table 3. UNICEF tender results for alternative versions of RUTF (2019) 23 List of figures

Fig. 1. Risk of bias of individual trials 12

Fig. 2. Meta-analysis of the rate of weight gain in grams per kilogram of

body weight per day 13

Fig. 3. Cumulative meta-analysis of the rate of weight gain in grams per

kilogram of body weight per day 14

Fig. 4. Subgroup meta-analysis of the rate of weight gain in grams per

kilogram of body weight per day 14

Fig. 5. Meta-analysis of recovery 15

Fig. 6. Cumulative meta-analysis of recovery 16

Fig. 7. Meta-analysis of time to recovery in days 16

Fig. 8. Meta-analysis of mortality 17

Fig. 9. Meta-analysis of default rates 17

Fig. 10. Meta-analysis of non-response 18

Fig. 11. RUTF macro cost breakdown 22

Fig. 12. Strategies to reduce the cost of treatment for severe acute malnutrition 24

CONteNtS

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Publication history

This is a new World Health Organization (WHO) guideline that updates the specific recommendation in the technical annex of the 2007 Joint Statement by WHO, the World Food Programme (WFP), the United Nations System Standing Committee on Nutrition (UNSSCN) and the United Nations Children’s Fund (UNICEF) on community-based management of severe acute malnutrition, which states that at least 50% of protein in ready-to-use therapeutic foods (RUTF) should come from dairy products.

The rigorous procedures described in the WHO handbook for guideline development, 2nd edition were followed in producing this guideline. This document presents the direct and indirect evidence that served to inform the recommendation herein.

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Acknowledgements

This guideline was coordinated by the World Health Organization (WHO) Actions in Health Systems Unit, Department of Nutrition and Food Safety. Dr Jaden Bendabenda and Zita Weise Prinzo prepared this document.

WHO acknowledges the technical guidance from the members of the WHO steering committee for this normative work (in alphabetical order): Mr Filiberto Beltran, Nutrition and Food Safety;

Sophie Boisson, Water, Sanitation and Hygiene; Bernadette Cappello, Essential Medicines;

Adelheid Marschang, Emergencies; Dr Jason Montez, Nutrition and Food Safety; Satoko Murakami, Nutrition and Food Safety; Adama Diop Ndiaye, Gender, Equity and Human Rights; Nigel Rollins, Maternal, Newborn, Child and Adolescent Health; and Pura Solon, Maternal, Newborn, Child and Adolescent Health; as well as Regional Advisors from all six WHO regions. The steering committee also acknowledges the leadership within the Department of Nutrition and Food Safety (Dr Francesco Branca, Dr Laurence Grummer-Strawn, and Dr Juan Pablo Peña-Rosas) for their guidance during the entire process.

WHO also acknowledges Nandi Siegfried for providing methodological advice and support throughout the guideline process.

We would like to express our gratitude to the WHO Guidelines Review Committee Secretariat and members of the Guidelines Review Committee for their technical support. Thanks also to Ms Alma Alic from the Department of Compliance, Risk Management and Ethics for her support in the management of the conflicts-of-interest procedures.

WHO gratefully acknowledges the technical input of the members of the guideline development group involved in this process, especially Janine Lewis for ably chairing the guideline development group meeting. We thank Dr Saskia de Pee, Dr Seni Kouanda, Professor Praveen Kumar and Dr Indi Trehan for peer reviewing the final document.

WHO is especially grateful to the following individuals for their support in conducting the systematic reviews used to inform this guideline (in alphabetical order): Robert Akparibo (Sheffield University, United Kingdom of Great Britain and Northern Ireland), Robert Bandsma (University of Toronto, Canada), Andrew Booth (Sheffield University, United Kingdom of Great Britain and Northern Ireland), Allison Daniel (University of Toronto, Canada), Isabel Potani (University of Malawi College of Medicine, Malawi, and University of Toronto, Canada) and Carolyn Spiegel- Feld (University of Toronto, Canada).

Financial support

WHO thanks the Eleanor Crook Foundation and Irish Aid for providing financial support for this work. The Clinton Health Access Initiative (CHAI) provided in-kind support for this work (a member of staff from CHAI supported the scoping review that informed the formulation of the PICO. The staff member is paid by the CHAI with no cost bearing to WHO). The WHO Department of Nutrition and Food Safety receives grants from donors; however, donors do not fund specific guidelines and do not participate in any decision related to the guideline development process, including the composition of research questions, membership of the guideline groups, conduct and interpretation of systematic reviews, or formulation of recommendations.

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Abbreviations

CI confidence interval

EPOC [Cochrane] Effective Practice and Organisation of Care [group]

FAO Food and Agriculture Organization of the United Nations GPW13 WHO’s Thirteenth General Programme of Work

GRADE Grading of Recommendations Assessment, Development and Evaluation GRADE-CERQual GRADE Confidence in the Evidence from Reviews of Qualitative research LAZ length-for-age Z-score

MUAC mid upper-arm circumference

PICO population, intervention, comparator and outcomes PROSPERO International Prospective Register of Systematic Reviews RCT randomized controlled trial

RoB 2 Version 2 of the Cochrane risk-of-bias tool for randomized trials

RR risk ratio

RUTF ready-to-use therapeutic foods SDGs Sustainable Development Goals SMD standardized mean difference UNICEF United Nations Children’s Fund

UNSSCN United Nations System Standing Committee on Nutrition WAZ weight-for-age Z-score

WHO World Health Organization

WFP World Food Programme

WLZ weight-for-length Z-score

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ix

WHO guideline ¹ on the dairy

protein content in ready-to-use therapeutic foods for treatment of uncomplicated severe acute malnutrition

Executive summary

Purpose of the guideline

This WHO guideline is an update of the specific recommendation in the technical annex of the 2007 Joint Statement by the World Health Organization (WHO), the World Food Programme (WFP), the United Nations System Standing Committee on Nutrition (UNSSCN) and the United Nations Children’s Fund (UNICEF) on community-based management of severe acute malnutrition, which states that at least 50% of the proteins in ready-to-use therapeutic foods (RUTF) should come from dairy products. When this Joint Statement was released, the only RUTF formulation available contained dairy as the primary source of protein. Recently, alternative RUTF formulations with different sources of protein have been tested in several trials. The aim of these alternative RUTF formulations is to reduce the production cost of RUTF by partially or fully replacing dairy protein with cheaper and/or locally available options. Reducing the cost of RUTF would increase access to treatment for children with severe acute malnutrition. This guideline provides global, evidence- informed recommendations focusing on whether reduced dairy or non-dairy RUTF should be used for treating uncomplicated severe acute malnutrition.

Guideline development methodology

WHO developed the present evidence-informed recommendations using the procedures outlined in the WHO handbook for guideline development, 2nd edition. The steps in this process include:

(i) identification of priority questions and outcomes; (ii) retrieval of the evidence; (iii) assessment and synthesis of the evidence; (iv) formulation of recommendations, including research priorities;

and planning for (v) dissemination; (vi) implementation, equity and ethical considerations; and (vii) impact evaluation and updating of the guideline. The Grading of Recommendations Assessment, Development and Evaluation (GRAde) methodology was followed to prepare evidence profiles related to preselected topics, based on up-to-date systematic reviews.

1 This publication is a World Health Organization (WHO) guideline. A WHO guideline is any document containing WHO recommendations about health interventions, whether clinical, public health or policy interventions.

A standard guideline is produced in response to a request for guidance in relation to a change in practice, or controversy in a single clinical or policy area, and is not expected to cover the full scope of the condition or public health problem. A recommendation provides information about what policy-makers, health care providers or patients should do. It implies a choice between different interventions that have an impact on health and that have ramifications for the use of resources. All publications containing WHO recommendations are approved by the WHO Guidelines Review Committee.

exeCutIve SummARY

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The initial scoping of the guideline was done by the guideline development group in a meeting held on 7 November 2019 via a virtual platform. The development and finalization of the evidence-informed recommendations were done by the guideline development group in a meeting held from 21 to 24 July 2020 via a virtual platform. Four experts served as technical peer reviewers of this guideline.

Available evidence

Three related key questions were formulated in the population, intervention, comparator and outcomes (PICO) format, when appropriate, as follows.

1. What is the effect of RUTF containing alternative sources of protein (non-dairy, or containing less than 50% of protein from dairy) compared to RUTF as specified by WHO (2007) (at least 50% of protein from dairy products) in terms of efficacy, effectiveness and safety in treating infants and children aged 6 months or older with uncomplicated severe acute malnutrition?

2. What is the effect of RUTF containing alternative sources of protein (non-dairy, or containing less than 50% of protein from dairy) compared to RUTF as specified by WHO (2007) (at least 50% of protein from dairy products) in terms of values and preferences (cultural, religious, etc.), inter/intra-household sharing, availability, acceptability, adherence, equity, (including gender-related issues), feasibility, accessibility and sustainability in treating infants and children aged 6 months or older with uncomplicated severe acute malnutrition?

3. What is the cost-effectiveness of RUTF containing alternative sources of protein (non-dairy, or containing less than 50% of protein from dairy) compared to RUTF as specified by WHO (2007) (at least 50% of protein from dairy products) in the cost of production (ingredients, quality control), cost per death averted, cost per disability-adjusted life year averted, as well as contribution of the RUTF formulation to the cost of delivery of the entire programme?

Does the cost-effectiveness vary significantly in different settings with different prevalence/

incidence of severe acute malnutrition, population density and coverage?

The available evidence included two systematic reviews (for questions 1 and 2) that followed the procedures in the Cochrane handbook for systematic reviews of interventions. There were no published trials on the cost-effectiveness of the interventions. The evidence on costs and resource implications for different RUTF formulations was taken from the UNICEF Supply Division, which compiles data of suppliers for medical commodities. The certainty of evidence for the outcomes ranged from very low to high, with all outcomes consistent in the direction favouring standard RUTF or no difference between the RUTF formulations with reduced/no dairy and standard RUTF. The guideline development group therefore determined the overall certainty across outcomes to be moderate.¹

An evidence-to-decision framework was used to lead discussion and decision-making. This included the following considerations: (i) the certainty of the evidence across outcomes critical to decision-making; (ii) the balance of benefits and harms; (iii) values and preferences related to the recommended intervention in different settings and for different stakeholders, including the populations at risk; (iv) the acceptability of the intervention among key stakeholders; (v) resource

1 According to GRADE, high certainty evidence indicates that we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty evidence indicates that we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty evidence indicates that our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty evidence indicates that we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

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exeCutIve SummARY implications for programme managers; (vi) equity; and (vii) the feasibility of implementation of

the intervention.

Recommendation and rationale Recommendation

Standard RUTF (with at least 50% of protein coming from dairy products) is recommended for outpatient treatment of children with severe acute malnutrition. Use of RUTF formulations with less than 50% of protein from dairy products for outpatient treatment of children with severe acute malnutrition is encouraged within research and evaluation settings (conditional recommendation;¹ moderate certainty of evidence).

Rationale

The available evidence was not enough to justify a change in the current recommendation that RUTF should have at least 50% of protein coming from dairy. The efficacy outcomes favoured the standard RUTF, while there were no robust data from producers to demonstrate that reducing the dairy content will reduce the costs and resource requirements of RUTF. The group therefore did not recommend the use of the reduced/no dairy formulations but noted the potential of these alternative formulations if more evidence of efficacy and cost-effectiveness is generated.

Research gaps

Discussions between the members of the guideline development group highlighted the research needed to provide further evidence, as follows.

 Continuing the search for alternative RUTF formulations with no dairy or less than 50% of protein from dairy products. Well designed studies are required to demonstrate further evidence of efficacy, cost-effectiveness and acceptability of different formulations, including considerations of age, breastfeeding status, severe acute malnutrition phenotype and geographical location, among others.

 Determining the optimal level of protein in RUTF beyond the current limits (10–12% of total energy), which were based on protein content in the habitual diets consumed by well nourished children in rich countries.

 Determining the optimal content of dairy products in RUTF. The minimum of 50% of protein in RUTF coming from dairy products set in the 2007 Joint Statement was chosen for practical reasons as it corresponded to what was already in the then existing and tested RUTF, but there is no evidence that 50% is the appropriate limit. Studies are needed to demonstrate whether increasing the proportion of protein from dairy in RUTF can lead to better outcomes.

 Determining the optimal dose of RUTF that is cost-effective. One potential strategy to reduce the cost of treatment for severe acute malnutrition is by reducing the dose or quantities of RUTF required for recovery; however, the efficacy and cost savings attributed to this strategy need to be demonstrated.

1 A conditional recommendation is one for which the guideline development group concludes that the desirable effects of adherence probably outweigh the undesirable effects, although the trade-offs are uncertain.

Implications of a conditional recommendation for populations are that while some people would desire the intervention, a considerable proportion would not. With regard to policy-makers, a conditional recommendation means that there is a need for substantial debate and involvement from stakeholders before considering the adoption of the intervention in each setting.

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1 Scope and purpose

SCOpe ANd puRpOSe This WHO guideline is an update of the specific recommendation in the technical annex of the

2007 Joint Statement by WHO, WFP, UNSSCN and UNICEF on community-based management of severe acute malnutrition, which states that at least 50% of the proteins in RUTF should come from dairy products (WHO, 2007). When this Joint Statement was released, the only RUTF formulation available contained dairy as the primary source of protein. Recently, alternative RUTF formulations with different sources of protein have been tested in several trials. The aim of these alternative RUTF formulations is to reduce the production cost of RUTF by partially or fully replacing dairy protein with cheaper and/or locally available options. Reducing the cost of RUTF would increase access to treatment for children with severe acute malnutrition.

Member States and United Nations partners requested WHO’s rigorous evaluation of the evidence on the efficacy of these innovative and novel RUTF formulations which have potential to increase coverage in the treatment of severe acute malnutrition in children. This guideline provides global, evidence-informed recommendations focusing on whether reduced dairy or non-dairy RUTF should be used for treating uncomplicated severe acute malnutrition.

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Background

The global burden of severe acute malnutrition

Globally, an estimated 14.3 million children aged 6–59 months suffered from severe acute malnutrition in 2019 (UNICEF, WHO & World Bank, 2020), defined as weight-for-length Z-score (WLZ) < –3 standard deviations and/or mid upper-arm circumference (MUAC) < 115 mm, and/or presence of bilateral pitting oedema (WHO, 2009). Child undernutrition is a major global health problem, contributing to child morbidity and mortality, impaired intellectual development, suboptimal adult work capacity and increased risk of diseases in adulthood (Black et al., 2013).

Malnourished children, particularly those with severe acute malnutrition, have a higher risk of death from common childhood illnesses, with 45% of deaths in children aged under 5 years attributed to malnutrition (UN IGME, 2019).

Most children aged 6 months or older with severe acute malnutrition can be safely treated in their communities without requiring admission to a health facility or a therapeutic feeding centre.

This community-based approach involves timely detection of severe acute malnutrition in the community, quick assessment of appetite, and treating those without medical complications with ready-to-use therapeutic foods (RUTF), combined with basic orally-administered medication to treat infections (WHO, 2007, 2013).

History of RUTF

Community-based management of children with uncomplicated severe acute malnutrition requires safe, palatable foods with a high energy content and adequate amounts of protein, vitamins and minerals, such as RUTF.

First developed in 1996, RUTF are soft or crushable foods that can be consumed easily by children from the age of 6 months without adding water. Prior to the development of RUTF, children with severe acute malnutrition were treated with F-100, a therapeutic formulation that requires preparation and administration by qualified health workers, used only in hospitals (WHO, 1999).

In contrast, RUTF can be used safely at home without refrigeration and even in areas where hygiene conditions are not optimal.

When there are no medical complications, a severely malnourished child who has appetite is given a standard dose of RUTF adjusted to their weight. Guided by appetite, the children consume the food at home, directly from the package, with supervision from their caregivers, at any time of the day or night. A child being treated for severe acute malnutrition generally requires a total of 10–15 kg of RUTF, consumed over a period of six to eight weeks (WHO, 2007).

Composition of RUTF

The most common formulation of RUTF (referred to as standard RUTF in this document) consists of four food ingredients (milk powder, peanut paste, vegetable oil and sugar) and multiple micronutrients to provide a complete complement of vitamins and minerals. The choice of food ingredients may be adjusted (usually by replacing peanuts with other legumes or cereals) depending on local availability, cost and acceptability, but the nutritional composition must comply with the 2007 Joint Statement (see Annex 1).

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3 Protein quality and quantity in RUTF

Protein requirements during recovery from severe acute malnutrition are higher than during periods of normal growth (Pencharz, 2010). Severe acute malnutrition is also associated with chronic intestinal dysfunction with reduced nutrient absorptive capacity (Attia et al., 2016). As such, both protein quality and quantity of therapeutic foods are important for optimal recovery from severe acute malnutrition. Protein quality refers to the digestibility, bioavailability and amount of each individual essential amino acid, whereas protein quantity refers to the total amount of protein.

In 2018, an Expert Working Group convened by the Food and Agriculture Organization of the United Nations (FAO) recommended that the protein in RUTF should be of adequate quantity and quality to support an average weight gain of 10 grams per kilogram of body weight per day for optimal recovery from severe acute malnutrition (FAO, 2018).

Alternative RUTF formulations

Milk is considered the most expensive ingredient in standard RUTF. As such, it is has been suggested that replacing dairy with alternative sources of protein can significantly reduce the costs of RUTF while maintaining the nutritional composition of RUTF recommended in the 2007 Joint Statement. These alternative formulations, if produced locally and at a lower cost, may improve scalability of treatment for severe acute malnutrition.

According to UNICEF categorization (UNICEF, 2019), alternative RUTF formulations can be grouped into three categories, as follows.

1. Renovation: products that use a combination of alternative cereals, legumes or grains as partial or full replacement to peanuts in the standard formulation, in addition to 50% protein sourced from dairy. These formulations are compliant with the 2007 Joint Statement.

2. Innovation: products that use a combination of cereals, legumes, grains and different sources of animal protein (e.g. fish, egg or insect protein) with reduced amounts of dairy protein or no dairy at all. These formulations do not comply with the 2007 Joint Statement.

3. Novel: products that use a combination of cereals, legumes or grains, and added amino acids and/or different amounts of added vitamins and minerals. These formulations do not comply with the 2007 Joint Statement.

Recently, these alternative RUTF formulations with different sources of protein have been tested in several trials. The primary aim of these alternative RUTF formulations is to reduce the production cost of RUTF by partially or fully replacing dairy protein with cheaper and/or locally available options.

Why is it important for WHO to develop this guideline?

Member States and United Nations partners requested WHO’s rigorous evaluation of the evidence on the efficacy of these innovative and novel RUTF formulations which have potential to increase coverage in the treatment of severe acute malnutrition in children.

The updated recommendation will help Member States and their implementing partners to make informed choices on different protein sources used in RUTF for the treatment of uncomplicated severe acute malnutrition. This is critical to efforts to achieve the World Health Assembly nutrition targets for 2025, which are incorporated into the Sustainable Development Goals (SDGs), to reduce and maintain wasting at < 5% (WHO, 2018b), as well as SDG target 3.2 to end preventable deaths of newborns and children under 5 years of age by 2030 (United Nations, 2020).

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WHO’s Thirteenth General Programme of Work (GPW13) 2019–2023 (WHO, 2019a) focuses on delivering impact for people at the country level, in all countries – low, middle and high income – and is based on the SDGs. The three strategic priorities set out in the GPW13, referred to as the

“triple billion” goals, are achieving universal health coverage, addressing health emergencies and promoting healthier populations. Nutrition, as a cross-cutting area in the health and development sectors, is an integral part of these goals (WHO, 2019a).

This is a new guideline that updates the specific recommendation in the technical annex of the 2007 Joint Statement by WHO, WFP, UNSSCN and UNICEF, which states that at least 50%

of protein in RUTF should come from milk products (WHO, 2007). This work will contribute to achieving WHO’s triple billion goals and the target for the reduction of wasting as given in the GWP13 impact framework.¹

Aim of the guideline

This guideline provides global, evidence-informed recommendations focusing on whether reduced dairy or non-dairy RUTF should be used for treating uncomplicated severe acute malnutrition. This document presents the key recommendation and a summary of the supporting evidence.

Target audience

The recommendations in this guideline are intended for a global audience, including health professionals, clinicians, researchers, managers of nutrition and health programmes, public health policy-makers and their expert advisers, and decision-makers in organizations involved in the production, procurement, distribution and prescription of RUTF for the outpatient management of severe acute malnutrition in humanitarian and other settings.

The end-users of this guideline are:

 national and local policy-makers;

 implementers and managers of national and local nutrition programmes;

 nongovernmental and other organizations and professional societies involved in the planning and management of severe acute malnutrition;

 health professionals including clinicians, researchers, managers of nutrition and health programmes and public health policy-makers in all settings;

 producers and suppliers of RUTF.

Scope

This WHO guideline is an update of the specific recommendation in the technical annex of the 2007 Joint Statement on community-based management of severe acute malnutrition by WHO, WFP, UNSSCN and UNICEF, which states that at least half of the protein contained in RUTF should come from milk products (WHO, 2007). Recently, alternative RUTF formulations with different sources of protein have been tested in several trials. The primary aim of these alternative RUTF formulations is to reduce the production cost of RUTF by replacing dairy protein with cheaper and locally available ingredients. Reducing the cost of RUTF would increase access to treatment for children with severe acute malnutrition. Using locally available ingredients may also boost local production of RUTF.

1 WHO’s GPW13 impact framework, targets and indicators, is available at:

https://www.who.int/about/what-we-do/Gpw13_wIF_targets_and_Indicators_english.pdf.

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5 Population of interest

The guideline will affect infants and young children aged 6 months or older with uncomplicated severe acute malnutrition globally.

Priority questions

Three related key questions were formulated in the population, intervention, comparator and outcomes (PICO) format, when appropriate, as follows.

1. What is the effect of RUTF containing alternative sources of protein (non-dairy, or containing less than 50% of protein from dairy) compared to RUTF as specified by WHO (2007) (at least 50% of protein from dairy products) in terms of efficacy, effectiveness and safety in treating infants and children aged 6 months or older with uncomplicated severe acute malnutrition?

2. What is the effect of RUTF containing alternative sources of protein (non-dairy, or containing less than 50% of protein from dairy) compared to RUTF as specified by WHO (2007) (at least 50% of protein from dairy products) in terms of values and preferences (cultural, religious, etc.), inter/intra-household sharing, availability, acceptability, adherence, equity, (including gender-related issues), feasibility, accessibility and sustainability in treating infants and children aged 6 months or older with uncomplicated severe acute malnutrition?

3. What is the cost-effectiveness of RUTF containing alternative sources of protein (non-dairy, or containing less than 50% of protein from dairy) compared to RUTF as specified by WHO (2007) (at least 50% of protein from dairy products) in the cost of production (ingredients, quality control), cost per death averted, cost per disability-adjusted life year averted, as well as contribution of the RUTF formulations to the cost of delivery of the entire programme?

Does the cost-effectiveness vary significantly in different settings with different prevalence/

incidence of severe acute malnutrition, population density and coverage?

Outcomes of interest

The following outcomes were considered important in evaluating the evidence for making the recommendations.

Effectiveness review:

 weight gain (or rate of weight gain);

 recovery (proportion recovered, time to recovery, sustained recovery);

 other outpatient therapeutic programme outcomes (default rate, relapse rate, non-response rate);

 mortality;

 anthropometry (mid-upper arm circumference [MUAC], weight-for-age Z-score [WAZ], weight-for-length Z-score [WLZ], and length-for-age Z-score [LAZ]);

 changes in body composition;

 biochemical changes.

Qualitative review:

 values and preferences;

 inter/intra-household sharing;

 availability;

 acceptability;

 equity;

 feasibility;

 accessibility;

 sustainability.

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Resource use review:

 costs and resource needs.

Assessment of certainty of evidence

For the effectiveness review, the Grading of Recommendations Assessment, Development and Evaluation (GRAde) approach was used to assess the certainty of evidence across outcomes (Balshem et al., 2011; Guyatt et al., 2011). The outcomes were assessed for within-trial risk of bias, directness of evidence, heterogeneity, precision of estimate effects and risk of publication bias. Each outcome was given a quality rating of high, moderate, low or very low, based on these criteria.

For the qualitative review, the GRADE Confidence in the Evidence from Reviews of Qualitative research (GRAde-CeRQual) approach was used to determine the overall certainty in the evidence considering methodological limitations, relevance, coherence and adequacy of the data (Lewin et al., 2018).

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7 Guideline development process

This guideline was developed in accordance with WHO’s evidence-informed guideline development procedures, as outlined in the WHO handbook for guideline development, 2nd edition (WHO, 2014).

Modern processes for guideline development require a rigorous, systematic assessment of the literature, incorporating an assessment of the certainty of evidence (WHO, 2014). Thus, generating the evidence supporting this guideline required a systematic search for trials and a meta-analysis of the available data to inform the recommendations.

WHO steering committee

A WHO steering committee, led by the Department of Nutrition and Food Safety, was established in 2019 with representatives from the departments of Maternal, Newborn, Child and Adolescent Health; Emergencies; Essential Medicines; Gender, Equity and Human Rights; Water, Sanitation and Hygiene; and Regional Advisors from all six WHO regions (Annex 9). The steering committee guided the overall guideline development process, including: drafting the scope of the guideline and key questions in PICO format; identifying the systematic review teams and guideline methodologist; developing the planning proposal; selecting the guideline development group, observers and peer reviewers; overseeing the evidence retrieval, assessment and synthesis;

collecting and assessing disclosures of interest; managing conflicts in consultation with the WHO Office of Compliance, Risk Management and Ethics; and convening a guideline development group meeting. After the recommendations were formulated by the guideline development group, the steering committee drafted the final guideline, including management of the peer review process. The steering committee will oversee the dissemination of the guideline.

Guideline development group

The guideline development group comprised 11 content experts with a range of technical skills in child health, nutrition, research and programmes, and with diverse perspectives, wide geographic representation and gender balance. The list of members of the guideline development group came from suggestions from WHO departments with an interest in the provision of scientific nutrition advice, WHO expert advisory panels, and previous guideline development group memberships.

The guideline development group advised WHO on: (i) the scope of the guidelines and priority questions for which systematic reviews of evidence would be commissioned; (ii) the choice of important outcomes for decision-making and developing recommendations; (iii) the interpretation of evidence with explicit consideration of the overall balance of risks and benefits;

and (iv) formulating the final recommendations, taking into account existing evidence as well as diverse values and preferences.

The first meeting of the guideline development group was held in November 2019 (virtually), where the group discussed the general scope, key questions and outcomes, and the systematic reviews required to answer the key questions. In preparation for this meeting, a scoping review was conducted by the steering committee and the report was shared with the guideline development group members.

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The second meeting of the guideline development group was held on 21–24 July 2020 (virtually), where the group examined the evidence available to inform the recommendation and appraised its certainty using the GRADE evidence profiles (Guyatt et al., 2013; Grade Working Group, 2018).

The group interpreted the evidence, taking into consideration the intervention benefits and harms, values, resources, equity, acceptability and feasibility criteria, to guide in formulating the recommendations (Guyatt et al., 2008; Brunetti et al., 2013; Andrews J et al., 2013; Andrews JC et al., 2013; WHO, 2014; Grade Working Group, 2018). The list of the guideline development group members and their areas of expertise appears in Annex 5.

Representatives of other United Nations entities and international organizations in the field of nutrition and child health also attended the two meetings as observers. The observers participated in technical presentations and in discussions related to those presentations, providing additional information, feedback and clarification when required. They did not participate in the decision- making process of formulating the recommendations. The list of observers and organizations they represent are shown in Annex 6.

Systematic review teams

The systematic review teams provided comprehensive, objective syntheses of the evidence for two of the key questions that informed the recommendation. The findings from the systematic reviews were shared with all guideline development group members in advance of the July 2020 meeting and also presented during the meeting. The reports of the systematic reviews have been submitted for publication in peer reviewed journals. The list of systematic reviews and authors is presented in Annex 7.

Management of conflicts of interests

The steering group, in compliance with the WHO guidelines for declaration of interests for WHO experts¹ and in collaboration with the WHO Office of Compliance, Risk Management and Ethics, managed the potential conflicts of interests. All potential guideline development group members were asked to fill in and sign the standard WHO declaration of interests and confidentiality undertaking forms. An updated curriculum vitae was also required from each prospective member of the guideline development group, as they participate in their individual capacity and not as institutional representatives.

The steering group reviewed the declarations of interest statements and the curriculum vitae to identify potential guideline development group members. Information from the internet or media were gathered to identify any public statements made or positions held by the prospective guideline development group members and experts on the topic of RUTF. These were assessed for intellectual bias that may be perceived to affect, or may affect, impartiality. All concerns or potential issues were discussed with the WHO Office of Compliance, Risk Management and Ethics. All potential conflicts of interest were managed on a case-by-case basis.

Upon review of the declarations of interests and consultation with the WHO legal department, one potential member was deemed to have conflicts of interest (having once received a research grant from the dairy industry) and therefore was excluded from the group. The rest of the potential members were deemed to have no perceived or real conflicts of interests on the topic.

At the beginning of both meetings of the guideline development group, the members were asked to verbally declare their conflicts of interest.

1 Guidelines for declaration of interests (WHO experts) are available at: https://www.who.int/about/ethics/doi- guide-eN.pdf?ua=1.

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9

The names of the guideline development group, along with a description of the objectives of the meeting, were published on the WHO website for public notice and comment (WHO, 2019b). No additional information on any interests or biases relating to the individuals being considered for membership of the guideline development group were brought to light during this public notice.

Identification of priority questions and outcomes

An initial set of questions to be addressed in the guidelines was the starting point for formulating the recommendation. The questions were drafted by technical staff in the Actions in Health Systems Unit of the Department of Nutrition and Food Safety. The questions were refined and finalized by the guideline development group in November 2019. The final key questions, along with the outcomes, are listed in PICO format in Annex 2.

The population of interest was infants and children aged 6 months or older with uncomplicated severe acute malnutrition; the intervention was any RUTF formulations containing less than 50% of protein coming from dairy (reduced/non-dairy RUTF); and the comparator was any RUTF formulations containing at least 50% of protein coming from dairy (standard RUTF).

Evidence identification and retrieval

The WHO Actions in Health Systems Unit of the Department of Nutrition and Food Safety commissioned systematic reviews for the evidence to inform the recommendations on this guideline. Two systematic review teams submitted successful proposals and the protocols were published in the International Prospective Register of Systematic Reviews (PROSPERO) (Booth et al., 2020; Daniel et al., 2020).

Quality assessment and grading of evidence

Systematic reviews based on the PICO questions were used to summarize and appraise the evidence. These reviews followed the procedures of the Cochrane handbook for systematic reviews of interventions (Higgins et al., 2020). Each trial included in the systematic reviews was assessed for risk of bias. This was recorded and contributed towards the assessment of the overall certainty of the evidence. During the discussion and deliberations, the guideline development group reviewed the certainty, scope and trial inclusion criteria for the systematic reviews. The relative weight given to the trials was considered when evaluating the certainty assessment for each trial. The findings were synthesized with a pooled estimate of effect. The results of the systematic reviews were presented to the guideline development group, along with an assessment of the confidence in the estimates of effect for all critical outcomes.

For the effectiveness outcomes, evidence profiles were prepared according to the GRADE approach to assess the overall certainty of the evidence (Balshem et al., 2011; WHO, 2014;

Grade Working Group, 2018). The certainty of evidence for each outcome was rated as “high”,

“moderate”, “low”, or “very low”, based on a set of criteria including risk of bias, inconsistency, imprecision, indirectness and publication bias.

For the qualitative outcomes, GRADE-CERQual assessments of the confidence associated with the findings were performed. The Cochrane Effective Practice and Organisation of Care (EPOC) template for qualitative evidence synthesis¹ was used to report the review methods.

1 EPOC template for qualitative evidence synthesis is available at: https://epoc.cochrane.org/news/qualitative- evidence-synthesis-template

GuIdelINe develOpmeNt pROCeSS

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Formulating the recommendations

The systematic reviews and the GRADE evidence profiles for each of the critical outcomes were used for formulating the recommendations. An evidence-to-decision framework was used to lead discussion and decision-making (Guyatt et al., 2008; Brunetti et al., 2013; Andrews J et al., 2013; Andrews JC et al., 2013; WHO, 2014; Grade Working Group, 2018). This framework, which considers discussions on key background information and criteria for making decisions and conclusions, was used to help the group to move from evidence to decisions.

For developing the recommendations, the guideline development group considered: the importance of the problem of severe acute malnutrition and the low treatment coverage; the evidence of the benefits and harms of the intervention compared to standard RUTF, and the certainty of this evidence; values and preferences; costs and resource requirements; and the equity, acceptability and feasibility of implementation.

Decision-making during the guideline development group meeting

The chairperson for the guideline development group was nominated at the opening of the meeting in July 2020 and the nomination was approved by the guideline development group.

An independent methodologist facilitated the meeting and discussions to formulate the recommendations.

The procedures for decision-making were established at the beginning of the meeting, including a minimal set of rules for agreement and documentation of decision-making and, in case of voting, that 60% of the members would constitute a majority. More than two thirds of the guideline development group were present and participated in formulating the recommendations. If there was no unanimous consensus (primary decision rule), more time was given for deliberations and the group reached a unanimous decision on the final recommendation. The remarks and concerns from each guideline group member were recorded and will be kept on file by WHO for up to five years.

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11 Evidence summary

To ensure that the recommendations are correctly understood and applied in practice, guideline users are encouraged to refer to the evidence summary and remarks, including the considerations on implementation.

Summary of the evidence

The evidence that informed this recommendation is based on two systematic reviews and data sourced from UNICEF. The purpose of the systematic reviews was to summarize the evidence on benefits and harms, the certainty of this evidence, values and preferences, costs and resource requirements, and the equity, acceptability and feasibility of using RUTF formulations with reduced or no dairy, compared to standard RUTF for treatment of uncomplicated severe acute malnutrition in children aged 6 months or older. The three key questions guiding the evidence review and synthesis for the recommendation are listed in the sections below. The questions and quantitative outcomes in a PICO format are presented in Annex 2.

Question 1. What is the effect of RUTF containing alternative sources of protein (non-dairy, or containing less than 50% of protein from dairy) compared to RUTF as specified by WHO (2007) (at least 50% of protein from dairy products) in terms of efficacy, effectiveness and safety in treating infants and children aged 6 months or older with uncomplicated severe acute malnutrition?

A systematic review was commissioned and registered in PROSPERO, number CRD42020160762 (Daniel et al., 2020). The full report of the systematic review can be accessed from the Advances in Nutrition journal (Potani et al., in press).

Eight articles, published from six different trials, were identified and included in this systematic review (Oakley et al., 2010; Irena et al., 2015; Bahwere et al., 2016, 2017; Sato et al., 2018; Sigh et al., 2018; Akomo et al., 2019; Hossain et al., 2019). All were individually randomized controlled trials (RCTs) apart from one cluster trial (Irena et al., 2015) with clustering at the health centre level, including a total of 24 health centres that were divided between the two trial arms.

These trials were conducted in three WHO regions, namely: Africa (Malawi [2 trials], Zambia and Democratic Republic of the Congo [1 trial each]); South-East Asia (Bangladesh [1 trial]), and the Western Pacific (Cambodia [1 trial]).

The alternative RUTF formulations used in the six trials were:

 soya RUTF containing 10% skim milk powder (Oakley et al., 2010);

 soya, maize and sorghum RUTF without dairy, used in two trials (Irena et al., 2015; Bahwere et al., 2016);

 soya, maize and sorghum RUTF without dairy but enriched with crystalline amino acids (trial arm 1), soya, maize and sorghum RUTF containing 9% skim milk powder (trial arm 2) (Bahwere et al., 2017);

 fish-based wafer RUTF without dairy (Sigh et al., 2018);

 soya RUTF without dairy (Hossain et al., 2019).

The characteristics of the six trials are summarized in Annex 3.

evIdeNCe SummARY

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A total of 4827 children aged 6–59 months were included from the six trials. The largest trial was by Oakley (1874 children) (Oakley et al., 2010) and the smallest trial was by Sigh (121 children) (Sigh et al., 2018).

Risk of bias of individual trials

Risk of bias was assessed using Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) which includes assessment of biases occurring due to the randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes and selection of the reported results (Sterne et al., 2019). Additional criteria examined for cluster RCTs included baseline imbalance, loss of clusters, incorrect analysis and comparability with RCTs (Sterne et al., 2019).

As shown in Fig. 1, the overall risk of bias was low but there was high risk of bias in the randomization process due to unblinding of participants and trial personnel and switching of some participants between the trial arms in two trials (Irena et al., 2015; Sigh et al., 2018).

High attrition in two trials led to some concerns of bias due to missing data (Sigh et al., 2018;

Hossain et al., 2019).

Fig. 1. Risk of bias of individual trials

D1 D2 D3 D4 D5 Overall

Oakley 2010

+ + + + + +

Irena 2015

+ x + – + x

Bahwere 2016

+ + + – + +

Bahwere 2017

+ + + – + +

Sigh 2018

+ x – – – x

Hossain 2019

+ + x + + –

Domains Judgement D1: Bias arising from the randomization process.

D2: Bias due to deviations from intended intervention.

D3: Bias due to missing outcome data.

D4: Bias in measurement of the outcome D5: Bias in selection of the reported result.

x High

– Some concerns

+ Low

The main outcomes reported in these trials were:

 weight gain (or rate of weight gain);

 recovery (and time to recovery);

 mortality;

 default rates;

 non-response;

 anthropometry outcomes (i.e. MUAC, WLZ, WAZ and LAZ);

 biochemical status;

 body composition.

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13 Weight gain

Weight gain (or rate of weight gain) was defined as gain in weight in grams per kilogram of body weight per day until recovery. The rate of weight gain was reported in all six trials. For all individual trials, apart from the Sigh 2018 trial, weight gain was significantly lower in children who consumed RUTF formulations with less than 50% of protein from dairy products compared to children who consumed standard RUTF based on Hedge’s g effect sizes. The meta-analysis results showed that the overall rate of weight gain was significantly lower in children who were given RUTF formulations with less than 50% of protein from dairy products compared to standard RUTF (standardized mean difference [SMD]: –0.20, 95% confidence interval {CI} [–0.26, –0.15], p < 0.001, I² = 0.0%) (Fig. 2). When excluding the Sigh 2018 trial, the only study with fish as an alternative source of protein to dairy, the meta-analysis estimates were similar (SMD: –0.2, 95% CI [–0.27, –0.15], p < 0.001, I² = 0.0%).

A cumulative meta-analysis was done to assess the trends in results over time with the development of new formulations of RUTF with less than 50% of protein from dairy products.

This approach demonstrates how the overall effect size changes as each individual trial is added to the meta-analysis, beginning with the earliest trial and adding trials by year (Leimu &

Koricheva, 2004; Clarke, Brice & Chalmers, 2014). In this meta-analysis, the effect size remained unchanged with the addition of each subsequent trial (Fig. 3).

Subgroup meta-analysis was also done to explore differences between non-dairy and low dairy versions of RUTF. The results were not different from the primary findings (i.e. compared to standard RUTF, the weight gain mean differences were –0.23 and –0.19 for non-dairy RUTF and reduced dairy RUTF, respectively) (Fig. 4).

The certainty of the evidence for weight gain was rated high according to the GRADE approach (Table 1).

evIdeNCe SummARY

Fig. 2. Meta-analysis of the rate of weight gain in grams per kilogram of body weight per day

Study RUTF < 50% Standard RUTF Hedges’s g

with 95% CI

Weight N Mean SD N Mean SD (%)

Oakley 2010 929 1.94 2.7 945 2.44 2.77 –0.18 [–0.27, –0.09] 42.36

Irena 2015 186 2.2 3.1 305 3.2 4.0 –0.27 [–0.45, –0.09] 10.42

Bahwere 2016 439 3.2 4.9 436 4.1 6.3 –0.16 [–0.29, –0.03] 19.82

Bahwere 2017 670 6.7 4.3 353 7.8 4.7 –0.25 [–0.38, –0.12] 20.86

Sigh 2018 37 1.08 1.0 38 1.06 1.1 0.02 [–0.43, 0.47] 1.74

Hossain 2019 105 3.9 3.2 108 5.2 4.6 –0.33 [–0.60, –0.06] 4.80

Overall –0.20 [–0.26, –0.15]

Heterogeneity: T² = 0.00, I² = 0.00%, H² = 1.00 Test of Θ_i = Θ_j: Q(5) = 3.33, p = 0.65

Test of Θ = 0: z = -6.78, p = 0.00

–0.5 0 0.5 Random-effects REML model

RUTF < 50% represents RUTF with less than 50% of protein coming from dairy products.

REML: restricted maximum likelihood.

Favours standard RUTF Favours RUTF < 50%

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Fig. 3. Cumulative meta-analysis of the rate of weight gain in grams per kilogram of body weight per day

Study Hedges’s g

with 95% CI

Oakley –0.18 [–0.27, –0.09]

Irena 2015 –0.20 [–0.28, –0.12]

Bahwere 2016 –0.19 [–0.26, –0.12]

Bahwere 2017 –0.20 [–0.26, –0.14]

Sigh 2018 –0.20 [–0.26, –0.14]

Hossain 2019 –0.20 [–0.26, –0.15]

–0.3 –0.25 –0.2 –0.15 –0.1

Fig. 4. Subgroup meta-analysis of the rate of weight gain in grams per kilogram of body weight per day

Study RUTF < 50% Standard RUTF Hedges’s g

with 95% CI

Weight N Mean SD N Mean SD (%)

Non-dairy

Irena 2015 186 2.2 3.1 305 3.2 4 –0.27 [–0.45, –0.09] 10.25

Bahwere 2016 439 3.2 4.9 436 4.1 6.3 –0.16 [–0.29, –0.03] 19.49

Bahwere 2017 (FSMS) 433 6.4 4.2 177 7.8 4.7 –0.32 [–0.50, –0.15] 11.12

Sigh 2018 37 1.08 1 38 1.06 1.1 0.02 [–0.43, 0.47] 1.71

Hossain 2019 105 3.9 3.2 108 5.2 4.6 –0.33 [–0.60, –0.06] 4.72

Heterogeneity: T² = 0.00, I² = 7.79%, H² = 1.08 –0.23 –0.32, –0.14]

Test of Θi = Θj: Q(4) = 3.99, p = 0.41 Low dairy

Oakley 2010 929 1.94 2.7 945 2.44 2.77 –0.18 [–0.27, –0.09] 41.66

Bahwere 2017 (MSMS) 420 6.8 4.5 176 7.8 4.7 –0.22 [–0.40, –0.04] 11.04

Heterogeneity: T² = 0.00, I² = 0.01%, H² = 1.00 –0.19 [–0.27, –0.11]

Test of Θi = Θj: Q(1) = 0.13, p = 0.72

Overall –0.21 [ –0.27, –0.15]

Test of group differences: Q_b(1) = 0.49, p = 0.48

–0.5 0 0.5

Random-effects REML model

FSMS: milk-free soya, maize and sorghum; MSMS: milk, soya, maize and sorghum; REML: restricted maximum likelihood.

Recovery

Recovery was reported in four trials (Oakley et al., 2010; Irena et al., 2015; Bahwere et al., 2016

& 2017), although defined differently in each of the trials, i.e. WLZ above –2 and no oedema (Oakley et al., 2010), and weight gain of at least 18%, MUAC above 110 mm and absence of oedema (Irena et al., 2015). The Bahwere et al. trials did not provide definitions of recovery, but in a previous trial, the authors defined recovery as weight gain of at least 15%, MUAC above 110 mm, absence of a medical complication, the absence of bilateral pitting oedema and a minimum stay in the programme of one month (Bahwere et al., 2014).

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15

evIdeNCe SummARY The evidence was mixed for individual trials, with two trials (Irena et al., 2015; Bahwere et

al., 2016) reporting lower recovery in children consuming RUTF formulations with less than 50% of protein from dairy products than in children consuming standard RUTF. The other two trials (Oakley et al., 2010; Bahwere et al., 2017) reported similar recovery rates between the intervention and the comparator based on the risk ratios (RRs). The meta-analysis showed that providing RUTF formulations with less than 50% of protein from dairy products resulted in fewer children recovering compared to standard RUTF (RR: 0.93, 95% CI [0.87, 1.00], p = 0.046, I²= 76.8%) (Fig. 5). Results from the cumulative meta-analysis across years showed similar effect sizes over time with the addition of each sequential trial (Fig. 6).

Four trials also examined the time to recovery (in days) (Irena et al., 2015; Bahwere et al., 2016 &

2017; Hossain et al., 2019). The Irena 2015 trial reported that the non-dairy RUTF was associated with a longer time to recovery compared to standard RUTF, but the other three trials did not show differences between the intervention and the comparator. The meta-analysis results indicated that the length of stay may be longer in children consuming RUTF formulations with less than 50% of protein from dairy products, although the difference was not significant (SMD: 0.20, 95%

CI [–0.01, 0.41], p = 0.06, I²= 83.3%) (Fig. 7).

None of the included trials examined sustained recovery because the follow-up periods were short (less than one year).

The certainty of the evidence for time to recovery was rated very low according to the GRADE approach (Table 1).

Fig. 5. Meta-analysis of recovery

Study

RUTF < 50%

Recovered Standard RUTF

Recovered Risk ratio

with 95% Cl

Weight (%)

Yes No Yes No

Oakley 2010 754 175 790 155 0.97 [0.93, 1.01] 30.48

Irena 2015 200 176 306 197 0.87 [0.78, 0.98] 17.08

Bahwere 2016 317 122 362 72 0.87 [0.81, 0.93] 25.03

Bahwere 2017 670 183 353 93 0.99 [0.94, 1.05] 27.40

Overall 0.93 [0.87, 1.00]

Test of Θ = 0: z = -2.00, p = 0.05

0.78 1 1.05

Random-effects REML model

REML: restricted maximum likelihood.

WHO guideline

guideline WHO

on the dairy protein content in ready-to-use therapeutic foods

for treatment of uncomplicated

severe acute malnutrition

guideline WHO

on the dairy protein content in ready-to-use therapeutic foods

for treatment of uncomplicated

severe acute malnutrition

iii

Contents

v

Publication history

vii

Acknowledgements

Financial support

Abbreviations

ix

WHO guideline 1 on the dairy

protein content in ready-to-use therapeutic foods for treatment of uncomplicated severe acute malnutrition

Executive summary

Purpose of the guideline

Guideline development methodology

Available evidence

xi

Recommendation and rationale Recommendation

Rationale

Research gaps

1

Scope and purpose

Background

The global burden of severe acute malnutrition

History of RUTF

Composition of RUTF

3

Protein quality and quantity in RUTF

Alternative RUTF formulations

Why is it important for WHO to develop this guideline?

Aim of the guideline

Target audience

Scope

5

Population of interest

Priority questions

Outcomes of interest

Assessment of certainty of evidence

7

Guideline development process

WHO steering committee

Guideline development group

Systematic review teams

Management of conflicts of interests

9

Identification of priority questions and outcomes

Evidence identification and retrieval

Quality assessment and grading of evidence

Formulating the recommendations

Decision-making during the guideline development group meeting

11

Evidence summary

Summary of the evidence

Risk of bias of individual trials

+ + + + + +

+ x + – + x

+ + + – + +

+ + + – + +

+ x – – – x

+ + x + + –

13

Weight gain

Recovery

15

WHO guideline ¹ on the dairy